Role of Prenatal Vitamin D Levels and Genetic Interactions in Autism Spectrum Disorders; Leveraging an existing case-control study Both vitamin D deficiency/insufficiency and autism spectrum disorders (ASD) have increased in prevalence over recent decades. Emerging evidence suggests vitamin D may be related to risk of ASD, particularly given recent advances in the understanding of the role of vitamin D on brain and immune function. In the proposed study, we will investigate the association between perinatal vitamin D deficiency/ insufficiency and ASD in the context of the existing Early Markers of Autism (EMA) study in order to leverage rich resources already collected. Specifically, this study aims to determine the association between maternal and neonatal vitamin D levels and risk of ASD, whether polymorphisms in genes related to vitamin D are associated with vitamin D levels and risk of ASD, and to test for interaction between vitamin D and genotype. Secondary aims are to examine whether risk differs according to subgroups, including child gender, phenotypic, and racial/ethnic groups, as well as to explore potential pathways linking vitamin D and ASD, specifically changes in immune marker levels and modification by, or interaction with, environmental toxins. The study will include ~550 children with autism, 200 with other intellectual disability (ID), and 440 unaffected children born in 2000-2003 in Southern California. ASD cases were ascertained from the California Department of Developmental Disabilities with record abstraction and confirmatory case classification based on expert clinician review. Genotyping of 2/3 of the study sample and measurement of markers of immune function and environmental exposures has already been conducted. In the proposed work, targeted genotyping of candidate genes in the remaining participants will be conducted, and vitamin D metabolites (25- hydroxyvitamin D2 and D3) will be measured using a highly sensitive laboratory methods in archived newborn blood spots and maternal serum samples. Mean levels of vitamin D will be compared across the primary study groups, and logistic regression will be used to calculate odds ratios of the association between vitamin D deficiency/insufficiency and risk of ASD, ID, and ASD+ID, adjusting for covariates from birth certificate and other EMA records. Main effects of polymorphisms and vitamin D levels will be calculated, while the interaction of these factors will be tested using logistic regression. Vitamin D levels will be compared by levels of measured toxins and immune markers, and mediating effects tested. This will be the first study with the ability to thoroughly examine the potential role of vitamin Din ASD by using quantified, in-utero and neonatal vitamin D levels, and to also consider genetic susceptibility and suspected pathways. We anticipate the results of this investigation will provide novel information about risk factors for ASD, and contribute to understanding of gene-environment interactions and underlying biology. By studying a common, modifiable exposure, this work could lead to the development of public health recommendations for prevention strategies to reduce the risk of ASD, which are currently lacking.